Recombinant Immunotherapy for Renal Cell Carcinoma

肾细胞癌的重组免疫疗法

• 批准号: 6901940
• 负责人: Thomas S Griffith
• 金额: $ 27.21万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901940
• 关键词: Adenoviridae; amidohydrolases; antigen presentation; apoptosis; biotechnology; collagen; dendritic cells; enzyme inhibitors; gelatin; gene delivery system; gene expression; gene therapy; immune response; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic cell; recombinant virus; renal cell carcinoma; therapy design /development; tissue /cell culture; transfection; transfection /expression vector; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Although many agents induce apoptosis, they are commonly associated with side effects that compromise health. TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L is generating excitement because it induces apoptosis in a wide range of tumor cells but not in normal cells and tissues. Preclinical studies using systemic TRAIL/Apo-2L doses are safe and can suppress tumor growth in vivo. Large amounts of TRAIL/Apo-2L are, however, needed to inhibit tumor formation, primarily because of the short in vivo half-life of the protein. Therefore, an alternative means of delivery may increase the relative activity of TRAIL/Apo-2L such that larger, more established tumors can be eradicated as efficiently as smaller tumors. This year in the U.S. approximately 30,000 new cases of renal cell carcinoma (RCC) will be diagnosed and nearly 12,000 deaths are expected from RCC. Metastatic RCC carries a median survival of 8 months and almost 30% of RCC patients are diagnosed with advanced metastatic disease. Furthermore, RCC is highly resistant to chemotherapy, a possible consequence of its association with the multidrug-resistance P-glycoprotein. RCC is regarded as an immunogenic tumor, with many reports of spontaneous regression and evidence of tumor-specific immune responses being a strong indicator of the immunogenicity of RCC. Thus, immunotherapy is being intensely studied as a treatment for RCC. Unfortunately, the response rates have been poor and significant toxicity reported, limiting the use of immunotherapy in the treatment of RCC. Gene transfer therapy offers new alternatives in the treatment of RCC. Employment of non-replicative viral gene delivery systems is making it possible to administer genes directly into tumors in situ. Previously, we described the cytotoxic activity of recombinant TRAIL/Apo-2L protein against human RCC cell lines, and the development and testing of a recombinant, replication-deficient adenoviral vector encoding the human TRAIL gene (Ad5-TRAIL). Transfer of the TRAIL gene into human tumor cells in vitro and in vivo, using immunodeficient mice, led to the rapid production and expression of TRAIL/Apo-2L protein, and apoptotic death of the tumor cells. However, it remains unknown whether Ad5-TRAIL will inhibit tumor growth in immunocompetent animals, and if the Ad5-TRAIL-induced tumor cell death will activate systemic antitumor immunity. With this in mind, the proposed project will employ a novel adenoviral vector encoding the mouse TRAIL gene (Ad5-mTRAIL) combined with agents to boost systemic immune responses through augmenting antigen presentation and stimulating T cell expansion to develop unique approaches for the treatment of RCC. Specific Aims: (1) Investigate the ability of DC to present antigens derived from apoptotic Renca cells to stimulate antitumor immunity and analyze the effector cells and mechanism of tumor rejection; and (2) Examine the ability of Gelfoam R and depsipeptide (FR901228) to augment Ad5-mTRAIL infectivity and transgene expression, making Ad5-mTRAIL gene transfer therapy more potent.

描述（由申请人提供）：尽管许多药物会诱导凋亡，但它们通常与损害健康的副作用有关。 TRAIL（与TNF相关的凋亡诱导配体）/Apo-2L引起兴奋，因为它在较大的肿瘤细胞中诱导凋亡，但在正常细胞和组织中却没有诱导凋亡。使用全身TRAIL/APO-2L剂量的临床前研究是安全的，可以抑制体内肿瘤的生长。但是，需要大量的TRAIL/APO-2L抑制肿瘤形成，这主要是由于蛋白质的体内半衰期短。因此，替代的递送方法可能会增加TRAIL/APO-2L的相对活性，从而可以像较小的肿瘤一样有效地消除较大，更具成熟的肿瘤。今年，在美国，将诊断出大约30,000例肾细胞癌（RCC）新病例，RCC预计将近12,000例死亡。转移性RCC的中位生存期为8个月，几乎30％的RCC患者被诊断出患有晚期转移性疾病。此外，RCC对化学疗法具有很高的抵抗力，这是其与多药耐药性P-糖蛋白相关的可能结果。 RCC被认为是一种免疫原性肿瘤，有许多自发消退的报道和肿瘤特异性免疫反应的证据是RCC免疫原性的有力指标。因此，作为RCC的治疗方法，正在深入研究免疫疗法。不幸的是，报告率较差，报道了明显的毒性，从而限制了免疫疗法在RCC治疗中的使用。基因转移疗法为RCC治疗提供了新的替代方法。非复制性病毒基因递送系统的使用使直接将基因直接用于原位肿瘤。以前，我们描述了重组TRAIL/APO-2L蛋白针对人RCC细胞系的细胞毒性活性，以及​​编码人类TRAIL基因（AD5-Trail）的重组，不存在的腺病毒载体的开发和测试。使用免疫缺陷型小鼠将径径基因的体外和体内转移到人体肿瘤细胞中，导致了TRAIL/APO-2L蛋白的快速产生和表达，以及肿瘤细胞的凋亡死亡。但是，尚不清楚AD5-Trail是否会抑制免疫能力动物的肿瘤生长，并且AD5-Trail诱导的肿瘤细胞死亡是否会激活全身性抗肿瘤免疫。考虑到这一点，拟议的项目将采用编码小鼠踪迹基因（AD5-MTRAIL）结合剂的新型腺病毒载体，通过增强抗原表现并刺激T细胞扩展来增强全身免疫反应，从而开发出独特的方法来治疗RCC。具体目的：（1）研究DC呈现源自凋亡Renca细胞刺激抗肿瘤免疫力并分析效应细胞的抗原的能力以及肿瘤排斥的机制； （2）检查Gelfoam R和Depsipeptide（FR901228）增强AD5-MTRAIL感染性和转基因表达的能力，从而使AD5-MTRAIL基因转移疗法更有效。